Alkynoxy-directed C-H functionalizations: Palladium(0)-catalyzed annulations of alkynyl aryl ethers with alkynes

Article abstract of DOI:10.1246/bcsj.20150180

Palladium(0)-catalyzed insertion/annulation sequence between aryl silylethynyl ethers and internal alkynes was found to proceed through activation of ortho-C-H bonds assisted by alkynoxy groups and gave stereoselectively (Z)-2-silylmethylenechromenes. The

Full text of DOI:10.1246/bcsj.20150180

Selected Paper
Alkynoxy-Directed C-H Functionalizations: Palladium(0)-Catalyzed
Annulations of Alkynyl Aryl Ethers with Alkynes
Yasunori Minami,*1,2 Yuki Shiraishi,3 Tatsuro Kodama,3 Mayuko Kanda,3
Kotomi Yamada,3 Tomohiro Anami,3 and Tamejiro Hiyama*1,2
1Research and Development Initiative, Chuo University, Kasuga, Bunkyo-ku, Tokyo 112-8551
2JST, ACT-C, Kasuga, Bunkyo-ku, Tokyo 112-8551
3Department of Applied Chemistry, Chuo University, Kasuga, Bunkyo-ku, Tokyo 112-8551
E-mail: yminami@kc.chuo-u.ac.jp, thiyama@kc.chuo-u.ac.jp
Received: May 29, 2015; Accepted: July 12, 2015; Web Released: July 22, 2015
Palladium(0)-catalyzed insertion/annulation sequence between aryl silylethynyl ethers and internal alkynes was
found to proceed through activation of ortho-C-H bonds assisted by alkynoxy groups and gave stereoselectively (Z)-2-
silylmethylenechromenes. These products could be easily converted into 2,2-alkylated 2H-chromene derivatives, an
important structural motif in medicinal chemistry and materials science. Various aryl silylethynyl ethers and alkynes can
be transformed under the reaction conditions, and a wide range of chromenes is thus accessible. When unsymmetric
alkynes are employed, a regioselective annulation takes place, especially those containing aryl and/or bulky substituents.
Catalytic systems based on palladium(0), such as Pd(OAc)2/PCy3/Zn, [Pd(dba)2]/PCy3, or Pd(PCy3)2 exhibit excellent
catalytic activity, and the best performance is observed for Pd(PCy3)2 in combination with Zn(OAc)2 as an additive.
Substituents on the aryl group in the alkynyl aryl ethers rarely affect the reaction rate. Deuterium-labeling experiments
suggest that the ortho-hydrogen atom migrates to the 2-methylene position in the chromene products. The cleavage of the
C-H bond is considered to be the rate-determining step in these reactions.
unsaturated substrates, e.g. in alkene polymerization and the
Mizoroki-Heck reaction,3 resulting in the formation of a broad
Introduction
The coordination of unsaturated carbon-carbon bonds to
metal complexes is one of the most fundamental reactions in
organometallic chemistry. It is also essential for synthetic
organic chemistry, as these unsaturated bonds become, upon
coordination to a high-valent metal complex, electrophilic
enough to react with nucleophiles (Scheme 1A). An example
for such a process is the nucleophilic attack of H2O to alkenes,
a key step in the Wacker oxidation.1 Also, such π-alkene/
alkyne metal complexes play a central role in the intra-
molecular hydroarylation with electron-rich aryl rings,2 and
they are susceptible to various insertion reactions of the
variety of σ-bound metal complexes (Scheme 1B). Recently,
coordination-assisted regioselective transformations in site-
selective C-C bond activation4 and hydrosilylation reactions
of alkynes have been reported (Scheme 1C).5 Although these
reactions proceed smoothly, this kind of coordination is rarely
employed for the activation of C-H bonds (Scheme 1D),6,7 i.e.
unsaturated bonds are act as directing groups with difficulty,
except in the case of the nitrile group.8
Alkynes usually coordinate to low-valent metal centers as
either electron donors or acceptors. Due to the strong back-
donation with the metal center, it is especially highly electron-
A) electrophilic activation
B) insertion
R M
R
M
M
Nu
M
Nu
C) selectivity
D) C-H activation
X
M
M
M
M H
C
H
C
X
M
X
X
X
X
Scheme 1. Coordination of unsaturated C-C bonds to metals.
1388 | Bull. Chem. Soc. Jpn. 2015, 88, 1388–1403 | doi:10.1246/bcsj.20150180
© 2015 The Chemical Society of Japan

O
δ-
R
Si
Mδn+
ii
O
α
Mn
O
O
β
R
R
Si
·
Si
alkynyl ether
Si
R = Ph
Mn+2
iv
Si
i
O
R
Mn+2
iii
Scheme 2. Low-valent transition-metal-catalyzed C-H activation reactions directed by alkynoxy groups.
MeO
O
Me
O
Me
Ph
MeO
MeO
N
OMe
4-Methoxylonchocarpene
Centchroman
O
O
R1
R4
Ph
HO
R5
Ph
O
O
OH
R2
R3
TRX-1
2,2-Diphenyl-2H-naphthopyran
Daurichromenic acid
Figure 1. 2H-Chromene and chromane moieties in functional compounds.
deficient alkynes such as dimethylacetylenedicarboxylate that
act as electron acceptors. We envisioned that highly polarized
alkynes should be able to act as electrophiles and hence interact
with nucleophilic low-valent transition metals, rendering these
metal centers sufficiently electrophilic in order to activate C-H
bonds. Accordingly, we decided to focus on oxygen-bound
alkynes, i.e. alkynyl ethers (Scheme 2).9 The ketene-like polari-
zed resonance structure (i) that characterizes the triple bond in
alkynyl ethers is well documented.10 In such structures, the α-
carbon atom is easily attacked by nucleophiles such as organo-
lithium reagents, thus indicating an electrophilic nature for the
α-carbon atom. Conversely, the β-carbon atom is sufficiently
basic to interact with a Lewis acid such as AuCl, and this dual
reactivity has been described in the context of several trans-
formations.9a,9b,9d,9l,9n,9q Our working hypothesis was based on
the notion that the coordination of an alkynoxy group to a low-
valent nucleophilic transition metal complex of e.g. nickel(0),
palladium(0), or platinum(0) may lead to the formation of an
electron-deficient metal center (ii), which may be in equilibrium
with a cationic metal(II) species (iii). An attack of the metal
center onto the α-carbon atom in the alkynyl ethers, followed
by the formation of aryl-metal bond (iv) via oxidative cleav-
age, could then result in a concerted metalation/deprotonation
or oxidative addition of Ar-H. In order to stabilize both the
cationic and anionic centers in such a putatively formed ketene-
like zwitterionic complex (i) and thus promote its formation, a
silyl group was introduced at the β-alkynyl carbon atom of the
substrate. Based on this idea, we were able to demonstrate a
palladium-catalyzed intramolecular hydrobenzylation, i.e. a
hydroarylation reaction of alkynyl ethers.11 Herein, we would
like to report details of this palladium-catalyzed double inser-
tion/annulation of alkynyl aryl ethers (1) with alkynes (2) via
activation of an ortho-C-H bond to give 2-silylmethylidene-2H-
chromenes.12,13 The 2H-chromene and chromane moieties in
e.g. centchroman or 4-methoxylonchocarpene represent impor-
tant structural motifs in medicinal chemistry and materials
science (Figure 1).14-24
Results and Discussion
The starting materials based on aryl silylethynyl ether (1)
were readily obtained from the treatment of aryl dichloro-
ethenyl ethers with a chlorosilane in the presence of a base.
Aryl dichloroethenyl ethers are accessible in high yields from
the reaction of phenols with trichloroethene.9d In our prelimi-
nary communication, we discussed a synthetic method that
involves the consecutive treatment of aryl dichloroethenyl
ethers with n-butyllithium in THF followed by chlorosilanes.
Unfortunately, substrates containing an electron-withdrawing
group are not accessible via this synthetic route. However, a
modification of the reaction conditions was able to overcome
this drawback. The use of diethyl ether as the solvent and
hexamethylphosphoramide (HMPA) as an additive or cosolvent
promoted the silylation of the electron-deficient substrate
(Scheme 3), and also gave previously prepared alkynyl aryl
Bull. Chem. Soc. Jpn. 2015, 88, 1388–1403 | doi:10.1246/bcsj.20150180
© 2015 The Chemical Society of Japan | 1389

1) BuLi (2.0 equiv)
Et2O (0.5 M)
-78 ~ -40 °C
O
2) TIPS-Cl (1.0 equiv)
HMPA (0.4 equiv)
-78 °C ~ rt
TIPS
MeO
R = MeO
1a, 90%
Cl2C=CHCl
(1 equiv)
NaOH (1 equiv)
Cl
OH
O
Cl
DMSO, rt
R
R
99% (R = MeO)
92% (R = CF3)
1) BuLi (2.0 equiv)
Et2O (1 M)
-78 ~ -40 °C
R = CF3
O
TIPS
2) TIPS-Cl (1.0 equiv)
HMPA (1.0 equiv)
-78 °C ~ rt
F3C
1b, 88%
Scheme 3. Preparation of alkynyl aryl ethers 1a and 1b.
ethers in improved yields. While the previous synthetic route
furnished e.g. p-methoxyphenyl-substituted triisopropylsilyl
(TIPS) ethynyl ether (1a) in 71% yield, the modified protocol
provided the target compound in 90% isolated yield. Moreover,
the modified conditions allowed us to prepare electron-deficient
alkynyl ethers such as 4-trifluoromethylphenyl TIPS ethynyl
ether (1b), which was obtained in 88% yield.
Pd(OAc)2 (5 mol%)
PCy3 (10 mol%)
Zn (5 mol%)
O
H
Si
toluene, 90 °C, 20 h
MeO
1a (Si = TIPS)
1c (Si = TBDPS)
Si
Si
Si
In order to evaluate the working hypothesis outlined in
Scheme 2, we examined the reaction of 1a with an in situ-
generated palladium(0) complex, and found the dimerization
to proceed smoothly. In the presence of Pd(OAc)2 (5 mol %),
PCy3 (10 mol %), and Zn (5 mol %), one molecule of 1a reacted
as a C-H bond cleaving agent, while a second acted as an
alkyne, generating a mixture of dimeric regioisomers 2a and
O
O
H
+
H
ð1Þ
MeO
O-PMP
MeO
Si
O-PMP
PMP = 4-MeO-C6H4
2a, 42%
2c, 98%
2'a, 38%
2'c, <2%
1
2¤a (53:47) in 80% overall yield as determined by H NMR
(eq 1). This result supported the notion that the alkynoxy
group may play a key role for the C-H activation (Scheme 2).
Bulky tert-butyldiphenylsilyl (TBDPS)-substituted alkynyl aryl
ether 1c furnished almost exclusively regioisomer 2c, bear-
Pd(OAc)2 (5 mol%)
PCy3 (10 mol%)
Zn (5 mol%)
O
tBu
toluene, 90 °C, 20 h
H
1
ing the TBDPS group at the 4-position (98% by H NMR), as
1d
steric repulsion between the TBDPS groups is thus minimized.
The structure of 2 was assigned on the basis of one- and
two-dimensional NMR spectroscopy (1H, COSY, NOESY,
and HMQC). However, all attempts to isolate 2 by column
chromatography or HPLC remained unsuccessful. The reac-
tion of 1d, bearing a t-Bu group on the alkynyl carbon atom
selectively formed C3-t-Bu-substituted 2¤d in 80% yield, while
the formation of 2d was not observed (eq 2). In this case, the
regioselectivity should probably be attributed to the steric
repulsion between the aryl and the t-Bu groups in 1. This result
suggested that carbonaceous groups on the alkynyl carbon atom
are also susceptible to such a C-H activation strategy. The
observed regioselectivity is in sharp contrast to the dimeriza-
tion of 1c, probably due to the insufficient spatial proximity of
the t-Bu groups during the insertion. Conversely, the dimeriza-
tion of 1d proceeded in the direction that avoids steric
repulsion between the t-Bu and aryl groups.
tBu
tBu
H
O
O
H
ð2Þ
+
tBu
O-m-tolyl
2'd, 80%
O-m-tolyl
tBu
2d, 0%
With a successful C-H activation method in hand, we aimed
at the intermolecular reaction between alkynyl aryl ethers (1)
and other alkynes. Initially, we examined the reaction of 1a
with 1-octyne (3), a representative terminal alkyne, under
conditions identical to eqs 1 and 2, as we envisioned that a
6-membered annulation product might be formed. However,
instead we isolated the alkynyl-C-H insertion product (Z)-(4-
MeO-C6H4O)(HexC¸C)C=C(TIPS)(H) (4) with perfect regio-
selectivity in 37% yield.12,25,26 It is worth noting that a 6-
1390 | Bull. Chem. Soc. Jpn. 2015, 88, 1388–1403 | doi:10.1246/bcsj.20150180
© 2015 The Chemical Society of Japan

Table 1. The reaction of 1a with 4-octyne (5a)a)
cat. M (5 mol%)
ligand (5-10 mol%)
additive (5 mol%)
TIPS
TIPS
H
O
O
O
H
+
Pr
Pr
+
TIPS
toluene, 90 °C, 2 h
MeO
O-PMP(TIPS)
MeO
H
MeO
Pr
TIPS(O-PMP)
Pr
1a
5a (1.5 equiv)
6aa
2a + 2'a
Entry
M
Ligand
Additive
6aa/%b)
2a + 2¤a/%b),c)
1
2
3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
[Pd(dba)2]
Pd(PCy3)2
PPh3
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
®
®
®
®
®
®
Zn
79
72
79
91
94 (86)
39
0
84
69
0
21
24
22
5
<1
35
0
16
31
0
P(o-tolyl)3
PPh2Cy
PPhCy2
PCy3
PBu3
PtBu3
dppf
4
5d)
6
7d)
8
9
DPEphos
®
10e)
11e)
12
13
14
15
16
17g)
PCy3
PCy3
®
0
0
92
94
85
0
28
(87)
<1
<1
<1
0
0
<1
Pd(PCy3)2 (0.5 mol %)
[Ni(cod)2]
Karstedt’s catalystf)
Pd(OAc)2
®
PCy3
PCy3
PCy3
a) Unless otherwise noted, a mixture of 1a (0.3 mmol), 5a (0.45 mmol), Pd (0.015 mmol), ligand (0.03 mmol for Entries 3-9, 12, and
13, 0.015 mmol for Entries 11 and 12), additive (0.015 mmol), decane (0.06 mmol), and toluene (0.3 mL) was heated at 90 °C for 2 h.
1
b) H NMR yield. Numbers in parenthesis represent isolated yields. c) Mixture of two regioisomers. d) 6 h. e) 38 h. f) Karstedt’s
catalyst = Pt[O{Si(Me)2CHCH2}2]. g) The reaction was examined on a gram-scale synthesis of 6aa. A mixture of 1a (1.21 g,
3.97 mmol), 5a (511 mg, 4.63 mmol), Pd(OAc)2 (45.3 mg, 0.202 mmol), PCy3 (113 mg, 0.403 mmol), Zn (13.5 mg, 0.207 mmol), and
toluene (4.0 mL) was heated to 90 °C for 12 h.
not formed
no reaction
H
O
O
OMe
Y
Pr TIPS
Pr
TIPS
MeO
TIPS
MeO
MeO
Pr
H
Pr
Y = CH2, 10
Y = C(O), 11
9
8
7
membered annulation was not observed, and that a screening of
catalyst, ligand, and additive loadings resulted in a maximum
yield of 86% for 4 (eq 3). The regioselectivity of the alkyne
addition can be feasibly explained on the basis of the metal-
alkyne interaction discussed in Scheme 2, i.e. a nucleophilic
attack of the alkynyl carbon atom on the α-carbon atom in 1.
Subsequently, we tested the reaction of internal alkynes with
1a in order to rule out a possible addition of an alkynyl-C-H
bond to the alkynoxy group. Therefore, we examined the
reaction of 1a with 4-octyne (5a) under various conditions
(Table 1). Initially, the reaction was carried out in the presence
of a catalytic amount of Pd(OAc)2, PPh3, and Zn in toluene at
90 °C for 2 h. Under these conditions, we were able to observe
the desired C-H activation, and the targeted product 6aa was
obtained in 79% yield, together with a mixture of the dimers 2a
and 2¤a in a combined yield of 21% (Entry 1; Table 1). The
formation of other potential reaction products, e.g. alkenylation
product 7, exo-cyclic 8, or alkyne trimers9e,9f,9j was not ob-
served. The structure of 6aa was unambiguously confirmed by
one- and two-dimensional NMR spectroscopy (1H, 13C, COSY,
NOESY, HMQC, and HMBC). To prevent the formation of
dimers, we examined various phosphine ligands and found that
tricyclohexylphosphine (PCy3) was able to give 6aa selectively
in 86% isolated yield (Entry 5; Table 1). The results of this
ligand screening suggested that a ligand with substantial steric
O
Pd(OAc)2 (5 mol%)
TIPS
DPPF (5 mol%)
Zn (5 mol%)
MeO
1a
+
toluene, 50 °C, 18 h
Hex
H
3 (1.1 equiv)
TIPS
H
O
ð3Þ
MeO
Hex
4, 86%
Bull. Chem. Soc. Jpn. 2015, 88, 1388–1403 | doi:10.1246/bcsj.20150180
© 2015 The Chemical Society of Japan | 1391

bulk is essential to suppress the formation of by-products and
to maintain the catalyst reactivity. Sterically less demanding
ligands such as PPhCy2 or PnBu3 as well as bidentate ligands,
including DPPF and DPEphos, generated substantial amounts
of 2a (Entries 2-4, 6, 8, 9; Table 1), while the significantly more
bulky ligand PtBu3 did not show any catalytic activity (Entry 7;
Table 1). In the absence of phosphine ligands, no reaction
occurred (Entry 10; Table 1). The purpose of the Zn additive is
to reduce palladium(II) to active palladium(0) (Entries 11-13;
Table 1), and in the absence of Zn, the formation of the desired
product 6aa was not observed. Reactions with palladium(0)
complexes such as [Pd(dba)2]/PCy3 or Pd(PCy3)2 furnished
6aa in 92 and 94% yield, respectively. A reduction of the
catalyst loading to 0.5 mol % still afforded 6aa in 85% yield
(Entry 14; Table 1). Using [Ni(cod)2]/PCy3 merely provided
trimeric acetylene adducts (Entry 15; Table 1). Platinum-based
Karstedt’s catalyst furnished 6aa in low yield (Entry 16;
Table 1). Consequently, we decided that the conditions using
Pd(OAc)2, PPh3, and Zn described in Entry 5 are the best for the
formation of 6 from the viewpoint of the yield and availability.
The best conditions (Entry 5; Table 1) could be successfully
used on a gram-scale reaction, which gave 6aa in 87% (1.43 g)
isolated yield (Entry 17; Table 1).
In order to evaluate the role of the alkynoxy group, we
attempted a reaction between 1,4-dimethoxybenzene (9) and
5a under the previously obtained optimized reaction condi-
tions. However, no product formation was observed. This
result stands in sharp contrast to the rhodium-catalyzed ortho-
alkenylation of anisole with internal alkynes and other oxygen-
directed C-H functionalizations.27-29 Still, methylene analog
10 and carbonyl analog 11 were recovered quantitatively,
indicating that the coordination of methoxy or basic carbonyl
moieties and isolated C¸C bonds is not capable of inducing a
comparable C-H activation and clearly demonstrated that the
presence of a highly polarized alkynoxy group is crucial for a
successful annulation.
The scope of the reaction between 1a and various internal
alkynes was examined under the optimized reaction conditions,
and the results are summarized in Table 2. Reactions using
diaryl-ethynes such as diphenylethyne (5b), di(3-thienyl)ethyne
(5c), or di(2-thienyl)ethyne (5d) gave 3,4-diaryl chromenes
6ab, 6ac, and 6ad, respectively, in moderate to high yields
(Entries 1-3; Table 2). 1,4-Bis(trimethylsilyl)-2-butyne (5e)
also smoothly reacted to furnish 6ae in 73% yield, and a
subsequent protodesilylation provided 12 after purification by
HPLC or column chromatography (Entry 4; Table 2). Bis(tri-
methylsilyl)ethyne (5f) afforded 6af in low yield, and the
observed predominant formation of 2a is probably due to the
steric hindrance (Entry 5; Table 2). The use of 4,4-dimethyl-2-
pentyne (5g) as a sterically biased alkyne resulted in the regio-
selective formation of 6ag, containing a t-Bu group at the 3-
position. In addition, by-product 13 was obtained in 27% yield.
The observed regioselectivity parallels that of the dimerization
of 1d. By-product 13 should be formed by the reaction with
tert-butylallene,13a derived from the in situ isomerization of 5g
(Entry 6; Table 2). In this case, the addition of 1a in portions
proved to be effective in order to reduce the dimerization of 1a.
The reaction with 1-phenyl-1-propyne (5h) exclusively gave
6ah in 70% yield, with the phenyl group located at the C4-
position (Entry 7; Table 2). The use of alkynes that contain
chlorine (5i) and functional groups such as tetrahydropyranyl
(5j), methoxycarbonyl (5k), and methoxymethyl (5l) group did
not hamper the reaction, and the use of PPhCy2 as a ligand
provided annulation products 6ai, 6aj, 6ak, and 6al, respec-
tively, albeit in lower regioselectivity. Regioisomers 6¤ai, 6¤aj,
6¤ak, and 6¤al were also obtained (Entries 8-11; Table 2). The
formation of these regioisomers may be attributed to the reduced
steric demand of PPhCy2. When PCy3 was used, no reaction was
observed for alkynes 5i-5l, probably due to an inhibition of the
insertion event. It should be noted that 6¤al could be converted,
after purification by HPLC and column chromatography on
silica gel, to 4-formyl product 14 via demethylation and aerobic
oxidation.
1-(p-Trifluoromethylphenyl)-3-methoxypropyne
(5m) provided 6am and 6¤am in 62% and 21% yield, respec-
tively (Entry 12; Table 2), suggesting that the presence of
electron-deficient aryl groups in 5 slightly favors the formation
of 4-arylated adducts relative to electron-donating ones. In the
case of phenyl(trimethylsilyl)ethyne (5n), annulation product
6an, bearing a bulky silyl group at the C3-position, was formed
exclusively in 60% yield (Entry 13; Table 2). Cyclopropyl-
(1-naphthyl)ethyne (5o) gave, under preservation of the cyclo-
propyl group, 6ao in 71% yield, whereby the cyclopropyl and 1-
naphthyl groups were incorporated at the C3- and C4-positions,
respectively, (Entry 14; Table 2).
Electronically biased diarylethyne 5p reacted with 1a to give
a mixture of 6ap and 6¤ap (1.6:1) in a combined yield of 96%
(eq 4). When 4-trifluoromethylphenyl-substituted alkynyl ether
1b was treated with 5p, a similar selectivity (1.8:1) was ob-
served, and 6bp, with a trifluoromethylphenyl group at the C4-
position, was obtained in 60% yield, while 6¤bp was formed
in 33% yield. These results suggested that electron-deficient
aryl groups are preferentially incorporated at the C4-position
in chromenes (Entries 11 and 12; Table 2). These results more-
over indicate that alkynoxyaryl groups are electron-rich, even if
electron-withdrawing substituents are attached to the aryl ring.
The electron-deficient aryl groups may be incorporated at the
C4-position as a result of π-stacking interaction during the
insertion.30
OMe
Pd(OAc)2 (5 mol%)
PCy3 (10 mol%)
Zn (5 mol%)
O
H
+
TIPS
toluene, 90 °C
R3
11 h
5p (1.5 equiv)
1a (R3 = OMe)
1b (R3 = CF3)
F3C
TIPS
H
TIPS
O
O
H
R3
R3
+
ð4Þ
CF3
OMe
CF3
OMe
6ap (R3 = OMe), 59%
6'ap, 37%
6'bp, 33%
6bp (R3 = CF3), 60%
Subsequently, we tested a broad variety of alkynyl aryl ethers
1 in this annulation (Table 3). Substrates containing silyl groups
such as TBDPS (1c), TBDMS (1e), or TES (1f) reacted with 5b
to form products 6cb, 6eb, and 6fb in 85%, 67%, and 56%
yields, respectively (Entries 1-3; Table 3). The structure of 6cb
was unambiguously determined by single-crystal X-ray dif-
1392 | Bull. Chem. Soc. Jpn. 2015, 88, 1388–1403 | doi:10.1246/bcsj.20150180
© 2015 The Chemical Society of Japan

Table 2. Scope of the internal alkynes (5) in insertion/annulation reactions with 1aa)
Pd(OAc)2 (5 mol%)
PCy3 (10 mol%)
Zn (5 mol%)
TIPS
H
TIPS
H
O
H
O
O
R1
R2
+
+
TIPS
toluene, 90 °C
MeO
MeO
R2
MeO
R1
R1
R2
1a
5 (x equiv)
6
6'
Time
/h
Entry
5
X
Product, Yield/%b)
TIPS
O
H
R
R
MeO
R
R
1
2
3
4
5
5b (R = Ph)
1.1
1.1
1.5
5
6
6
6
6
13
6ab, 92
6ac, 50
6ad, 87
6ae, (73)c)
6af, 23
5c (R = 3-thienyl)
5d (R = 2-thienyl)
5e (R = CH2TMS)
5f (R = TMS)
5
TIPS
H
O
6d)
6
23
6
5g
MeO
MeO
6ag, 37e)
TIPS
H
TIPS
O
O
H
+
Ar
R2
1.1
R2
MeO
Ar
Ar
R2
6ah-6am
6ah, 70
6ai + 6¤ai, 75 + 2 (97:3)
6¤ah-6¤am
7
5h (Ar = Ph, R2 = Me)
5i (Ar = 4-MeOC6H4, R2 = (CH2)4Cl)
5j (Ar = 4-MeOC6H4, R2 = (CH2)2OTHP)
5k (Ar = 4-MeOC6H4, R2 = (CH2)3CO2Me)
5l (Ar = 4-MeOC6H4, R2 = CH2OMe)
5m (Ar = 4-CF3C6H4, R2 = CH2OMe)
1.1
1.1
1.1
1.1
1.1
1.1
6
2
24
2
10
10
8f)
9f)
6aj + 6¤aj, 60 + 13 (82:18)
6ak + 6¤ak, 53 + 5 (91:9)
10f)
11f)
12f)
6al + 6¤al, 55 + (29)c) (65:35)
6am + 6¤am, 62 + (21)c) (75:25)
TIPS
O
H
13
1.1
6
Ph
TMS
5n
MeO
MeO
TMS
6an, 60
6ao, 71
Ph
O
TIPS
H
14
1.1
16
5o
a) Unless otherwise stated, a mixture of 1a (0.5 mmol), 5, Pd(OAc)2 (0.025 mmol), PCy3 (0.05 mmol), Zn (0.025 mmol), and
toluene (0.5 mL) was heated to 90 °C. b) Isolated yield. c) 1H NMR yield. d) 1a was added in six portions (1 h intervals). e) 13
was generated in 27% yield. f) PPhCy2 was used instead of PCy3. TMS: trimethylsilyl; THP: tetrahydropyranyl.
SiiPr3
TIPS
TIPS
H
O
O
O
H
H
TMS
MeO
MeO
MeO
Me
tBu
H
O
OMe
12
13
14
fraction analysis. In order to examine the size effect of the
silyl group, tert-butylethynyl aryl ether 1d was subjected to a
reaction with 5a. However, only the formation of dimer 2¤d in
88% yield (1H NMR) was observed, while the 1:1 annulated
product was not obtained. Conversely, trimethylsilylalkynyl
ether p-MeOC6H4OC¸CTMS and 1-propynyloxy ether p-
Bull. Chem. Soc. Jpn. 2015, 88, 1388–1403 | doi:10.1246/bcsj.20150180
© 2015 The Chemical Society of Japan | 1393

MeOC6H4OC¸CMe did not afford the annulated products 6 nor
dimers 2. These results suggested that ethynoxy groups with a
bulky substituent should act as the directing group for an ortho-
C-H activation and that the intermolecular annulation with
other alkynes should require the steric repulsion arising from
silyl substituents (e.g. TIPS, TBDPS, or TES) that have an
increased steric demand relative to carbonaceous substituents
such as tert-butyl substituents. A variety of substituted phenyl
groups could be used in combination with a TIPS-substituted
ethynoxy group for the reaction with 5a. For example, 4-
tolyloxy- and phenoxyethyne 1g and 1h furnished 6ga and
6ha (Entries 4 and 5; Table 3). Fluorine and trifluoromethyl
substituents at the 4-position on the phenyl ring did not interfere
significantly with the reaction and gave 6ia and 6ba (Entries
6 and 7; Table 3). In case of meta-substituted aryl moieties,
bearing methoxy (1j), methyl (1k), trifluoromethyl (1l), or
biphenyl (1m) groups, the annulation proceeded at the less
hindered ortho-position to provide 6ja, 6ka, 6la, and 6ma in
good yields (Entries 8-11; Table 3). In contrast, meta-fluoro-
phenyl alkynyl ether 1n furnished 5-fluorochromene 6na(5-F)
as the main product. This site selectivity may be attributed to
the coordination of lone pair electrons of fluorine to palladium
(Entry 12; Table 3).31 Similar regioselective fluorine-directed
C-H functionalizations have precedents, e.g. the ortho-C-H
cleavage of fluorobenzene,27a or the ruthenium-mediated ortho-
C-H activation of acetophenone.32 Aryl ethers, carrying an
ortho-substituent, such as 1o (R = Me) and 1p (R = Ph) were
able to give 6oa and 6pa (Entries 13 and 14; Table 3), while
silylethynyl 1-naphthyl and 2-naphthyl ethers 1q and 1r pro-
vided 6qa and 6ra in 80% and 81% yield, respectively (Entries
15 and 16; Table 3). It should be noted that the 3-C-H bond in
1r was activated selectively, probably due to steric constraints
at the peri-position of the naphthyl ring.
strated that the reaction of alkynyl aryl ethers with allenes
proceeded regioselectively to give 2,3-bismethylidene-chroma-
nes.13a On the basis of this finding, we achieved the annulation
of alkynyl aryl ethers with norbornene (17a) and norbornadiene
(17b) and the results are summarized in Table 4.33 When the
reaction of TIPSethynyl p-methoxyphenyl ether (1a) with
5 equiv of norbornene (17a) was performed under the con-
ditions {[Pd(dba)2] and PCy3 at 100 °C or Pd(PCy3)2 at 70 °C}
for the reaction with alkynes, ortho-C-H insertion/annulation
product 18aa was afforded in low yield (Entries 1 and 2;
Table 4). This examination suggested that Pd(PCy3)2 catalyst
is more effective than the combination of [Pd(dba)2] and PCy3
probably due to coordination of released DBA to the palladium
center, interfering the reaction of norbornene with palladium
catalysts. Of many conditions examined, we found that the
yield of 18aa was improved to 54% when the reaction was
carried out at 70 °C for longer reaction time with catalytic
amount of Zn (5 mol %) as an additive (Entry 3; Table 4). It is
assumed that metallic Zn cocatalyst prevents deactivation of
Pd(0) by reducing once-generated palladium(II) species to the
catalytically active palladium(0) complex, and/or effects the
formation of polarized or zwitterionic complex ii or iii (cf.
Scheme 2). Higher reaction temperature (120 °C) shortened
the reaction time with a similar yield of 18aa (51% isolated
yield) (Entry 4; Table 4). The conditions using {Pd(PCy3)2 and
Zn(OAc)2 or Pd(OAc)2, PCy3, and Zn} also showed similar
rate acceleration but decreased the yield of 18aa (Entries 5 and
6; Table 4).34 Various aryl silylethynyl ethers were applied to
the Pd(0)-catalyzed annulation with 17a at 100 °C under the
conditions of run 4 and the results are summarized in Table 4.
Substrates 1c and 1e having such a silyl group as TBDPS and
TBDMS on alkynyl carbons reacted with 10 equiv of 17a to
give 18ca and 18ea in 40% and 27% yields, respectively
(Entries 7 and 8; Table 4). In these cases, use of low equiv-
alents of 17a generated dimers 2. 18ca and 18ea could not be
isolated due to their instabilities. Various substrates with such a
substituent as p-methyl (1g), unsubstituted (1h, R3 = H), p-
trifluoromethyl (1b), and m-methyl (1k), on the aryl group gave
the corresponding products in moderate yields (Entries 9-12;
Table 4). In the case of 3-tolyl ether 1k, less-hindered 6-C-H
bond only participated in the reaction to give 18ka (Entry 12;
Table 4). The structure of 18ba was unambiguously deter-
mined by single-crystal X-ray diffraction analysis (Figure 2).35
Norbornadiene (17b) was used for the reaction with 1h and
obtained mono annulation product 18hb as a monomer mono-
mers for ring-opening metathesis polymerization (Entry 13;
Table 4).36
Having established this annulation protocol, we subsequent-
ly investigated double annulations of bisalkynoxyarenes for
the synthesis of polycondensed heterocycles. For example, the
reaction of 1,4-dialkynoxybenzene 15 with 4-octyne (5a) or
diphenylethyne (5b) proceeded smoothly to give condensed
tricycles 16a and 16b in excellent yields (eq 5). In both cases,
the hydrogen atoms at the 2,5-position were activated to
provide linearly condensed heteroaromatics. This result demon-
strated the utility of the present reaction for the synthesis of C2-
symmetric condensed cycles.
H
O
TIPS
+
R
R
TIPS
H
O
5 (3.0 equiv)
15
In order to gain further insight into the reaction mechanism,
deuterium-labeling experiments were carried out. We chose
Pd(PCy3)2 as the catalyst for the following experiments, which
was assumed to proceed cleanly and smoothly at the initial
stage of the reaction without an induction period. According to
Pd(OAc)2 (5 mol%)
PCy3 (10 mol%)
Zn (5 mol%)
R
TIPS
H
R
O
ð5Þ
H
toluene, 90 °C, 6 h
R
O
1
the H NMR analysis, 6ha-d5 was obtained from the reaction
TIPS
R
between pentadeuteriophenyl TIPSethynyl ether 1h-d5 and 5a
in toluene. This result suggested that the deuterium atom that is
initially located in the ortho-position was almost quantitatively
transferred onto the 2-(E)-methylidene position (eq 6). This
result furthermore indicated an oxidative addition of the ortho-
C-H bond onto a palladium(0) complex to provide an aryl
16a (R = Pr), 90%
16b (R = Ph), 96%
We next investigated application of this insertion/annulation
sequences to alkenes to form 1-chromanes as an important
structural motif for biological chemistry. Recently, we demon-
1394 | Bull. Chem. Soc. Jpn. 2015, 88, 1388–1403 | doi:10.1246/bcsj.20150180
© 2015 The Chemical Society of Japan

Table 3. Scope of the alkynyl aryl ethers (1) in insertion/annulation sequences with the internal alkynes (5)a)
Pd(OAc)2 (5 mol%)
R4
PCy3 (10 mol%)
Zn (5 mol%)
O
H
O
H
R3
R1
R2
R3
+
R4
toluene, 90 °C, 6 h
R2
R1
1
5 (x equiv)
6
Entry
1
5
x
Product, Yield/%b)
R4
O
H
O
H
R4
MeO
MeO
Ph
Ph
1
2
3c)
1c (R4 = TBDPS)
1e (R4 = TBDMS)
1f (R4 = TES)
5b
5b
5b
1.5
6
6
6cb (R4 = TBDPS), 85
6eb (R4 = TBDMS), 67
6fb (R4 = TES), 56
TIPS
O
H
O
TIPS
R3
H
R3
Pr
Pr
4
5
6
7
1g (R3 = Me)
1h (R3 = H)
1i (R3 = F)
5a
5a
5a
5a
1.1
1.1
1.5
1.5
6ga (R3 = Me), 90
6ha (R3 = H), 82
6ia (R3 = F), 83
6ba (R3 = CF3), 85
TIPS
1b (R3 = CF3)
R3
O
R3
O
H
H
TIPS
Pr
Pr
8
9
10
11d)
1j (R3 = MeO)
1k (R3 = Me)
1l (R3 = CF3)
5a
5a
5a
5a
1.1
1.5
1.5
1.1
6ja (R3 = MeO), 72
6ka (R3 = Me), 73
6la (R3 = CF3), 68
6ma (R3 = 2-Ph-C6H4), 63
TIPS
1m (R3 = 2-Ph-C6H4)
TIPS
H
O
F
O
H
F
O
H
+
12
5a
1.5
Pr
Pr
TIPS 1n
F
Pr
Pr
6na(5-F) + 6na(7-F), 68 + 5
R3
TIPS
R3
O
O
H
H
TIPS
Pr
Pr
13
14
1o (R3 = Me)
1p (R3 = Ph)
5a
5a
1.1
5
6oa (R3 = Me), 60
6pa (R3 = Ph), 84
TIPS
O
H
O
H
15
16
5a
5a
1.5
1.5
Pr
Pr
TIPS 1q
6qa, 80
TIPS
O
O
H
H
TIPS 1r
Pr
6ra, 81
Pr
a) Unless otherwise stated, a mixture of 1 (0.5 mmol), 5, Pd(OAc)2 (0.025 mmol), PCy3 (0.05 mmol), Zn
(0.025 mmol), and toluene (0.5 mL) was heated to 90 °C. b) Isolated yield. c) In toluene (2.0 mL); t = 3 h.
d) T = 120 °C; t = 12 h. TBDMS: tert-butyldimethylsilyl; TES: triethylsilyl.
palladium hydride complex, which would subsequently be
subjected to bimolecular insertion of two C¸C bonds. The
relative reaction rate (kH/kD) of 1h vs. 1h-d5 was measured at
90 °C (5 h) in C6D6, and provided a value of 2.28 (eq 7). An
Bull. Chem. Soc. Jpn. 2015, 88, 1388–1403 | doi:10.1246/bcsj.20150180
© 2015 The Chemical Society of Japan | 1395

Table 4. Pd(PCy3)2-catalyzed double insertion/annulation sequence of 1 with 17a)
Pd cat. (5 mol%)
ligand (10 mol%)
additive (5 mol%)
Si
O
O
7
6
3
H
R3
R3
+
Si
toluene, 100 °C
4
H
1
17
18
Entry
Pd/ligand/additive
1
17
Time/h
18
Yield/%b)
Si
O
O
H
Si
MeO
H
MeO
1
Pd(dba)2/PCy3/®
Pd(PCy3)2/®/®
Pd(PCy3)2/®/Zn
Pd(PCy3)2/®/Zn
Pd(PCy3)2/®/Zn(OAc)2
Pd(OAc)2/PCy3/Zn(OAc)2
Pd(PCy3)2/®/Zn
Pd(PCy3)2/®/Zn
1a (Si = TIPS)
1a
1a
1a
1a
1a
17a
17a
17a
17a
17a
17a
17a
108
134
87
12
12
13
20
20
18aa (Si = TIPS)
(5)
(13)
(54)
2c)
3c)
4d)
5d)
6d)
7e)
8e)
18aa
18aa
18aa
18aa
18aa
51 (57)
(51)
(21)
(40)
(27)
1c (Si = TBDPS)
1e (Si = TBDMS)
18ca (Si = TBDPS)
18ea (Si = TBDMS)
TIPS
17a
O
3
O
7
R3
H
R3
TIPS
4
H
6
9
10
11
12
Pd(PCy3)2/®/Zn
Pd(PCy3)2/®/Zn
Pd(PCy3)2/®/Zn
Pd(PCy3)2/®/Zn
1g (R3 = 4-Me)
1h (R3 = H)
1b (R3 = 4-CF3)
1k (R3 = 3-Me)
17a
17a
17a
17a
13
11
12
13
18ga (R3 = 6-Me)
18ha (R3 = H)
18ba (R3 = 6-CF3)
18ka (R3 = 7-Me)
62
56
45
44
TIPS
O
H
O
H
13
Pd(PCy3)2/®/Zn
17b
8
72
TIPS 1h
18hb
a) Unless otherwise noted, a mixture of 1 (0.5 mmol), 17 (2.5 mmol), Pd(PCy3)2 (0.025 mmol), Zn (0.025 mmol), and toluene (0.5 mL)
was heated at 100 °C. b) Isolated yield. Numbers in parenthesis are NMR yields. c) 70 °C. d) 120 °C. e) 17a (10 equiv).
Pr
Pr
intermolecular competition experiment between 1h and 1h-d5
with 5a gave 6ha and 6ha-d5 in a 4.6:1 ratio (eq 8). The
reaction of 1g-d1, containing deuterium at the ortho-position,
with 5a at 90 °C (6 h) in C6D6 formed both hydrogen- and
deuterium-cleaved products 6ga(8-D) and 6ga(α-D) in a 3.2:1
ratio (eq 9). Consequently, the C-H bond cleavage was
identified as the rate-determining step.37 This conclusion is in
stark contrast to the Ru-catalyzed C-H activation of methyl
benzoate,38 thus suggesting that the alkynoxy group does not
merely act as an intramolecular coordination moiety, but that
such a ligation also enhances the reactivity of the palladium
complex to accelerate the oxidative addition of the C-H bond.
(5a, 1.5 equiv)
O
X
Pd(PCy3)2 (5 mol%)
X4
TIPS
C6D6, 90 °C, 1.5 h
kH/kD = 2.28
1h (X = H)
1h-d5 (X = D)
TIPS
X
O
ð7Þ
X4
Pr
Pr
6ha (X = H)
6ha-d5 (X = D)
O
Pd(OAc)2 (5 mol%)
PCy3 (10 mol%)
Zn (5 mol%)
TIPS
O
D4
TIPS
1h-d5
D
+
H/D
O
toluene, 90 °C, 6 h
Pr
Pr
Pr
TIPS
H
1h (0.5 equiv)
Pr
Pr
(5a, 1.5 equiv)
Pr
6ha
+
Pd(PCy3)2 (5 mol%)
5a (1.5 equiv)
+
TIPS
D
C6D6, 90 °C, 2 h
TIPS
H/D
O
O
O
ð6Þ
D4
ð8Þ
D4
D4
TIPS
Pr
Pr
D
>93% D
Pr
6ha-d5
Pr
1h-d5 (0.5 equiv)
6ha-d5, 86%
6ha : 6ha-d5 = 4.6 : 1
1396 | Bull. Chem. Soc. Jpn. 2015, 88, 1388–1403 | doi:10.1246/bcsj.20150180
© 2015 The Chemical Society of Japan

The reaction of 1h-d5 with norbornene 17a in toluene under
best conditions for the formation of 18 (cf. Entry 4; Table 4)
1
resulted in the formation of 18ha-d5 as analyzed by H NMR,
demonstrating that the original ortho-deuterium was selectively
shifted to the silylethenyl group (eq 11). At least, this experi-
ment suggests that the formation of 18 by the palladium(0)
catalyst is achieved as is the case with the mechanism of the
reaction with alkynes.
O
D4
TIPS
D
Pd(PCy3)2 (5 mol%)
Zn (5 mol%)
1h-d5
+
toluene, 100 °C, 7 h
17a (5 equiv)
TIPS
H/D
O
Figure 2. Molecular structure of 18ba. Thermal ellipsoids
are set at 50% probability and hydrogen atoms are omitted
for clarity.
ð11Þ
D4
95% D
18ha-d5, 48%
Subsequently, we carried out kinetic studies in order to
evaluate the electronic effect of the aryl group in 1. Reactions
of 1a (4-MeO), 1b (4-CF3), 1j (3-MeO), and 1l (3-CF3) with
5a in the presence of catalytic amounts of Pd(PCy3)2 were
monitored by GC, and the yield of the corresponding products
6 was plotted as a function of the reaction time (Figure 3).
Depending on the substituent at the 4-position, minor rate
differences were observed for the formation of 6, i.e. 1b
(4-CF3) reacted slightly faster with 5a than 1a (4-MeO)
(Figure 3a). Conversely, no significant difference was observed
between 1j and 1l (Figure 3b). These results demonstrated that
the rate-determining step (C-H cleavage) is influenced by the
presence of an electron-withdrawing substituent in the C4-
position of 1. Again, this is in opposition to the oxidative cleav-
age of aryl C-H bonds by high-valent palladium complexes,
i.e. an electrophilic attack of electron-deficient metal com-
plexes onto arenes.39
Competition reactions between MeO- and CF3-substituted
substrates (1a vs. 1b, 1j vs. 1l) preferentially formed products
with CF3-substitutents in both 4- and 3-position (Figure 4),
which is in contrast to the case described in Figure 3b. This
effect may be attributed to the presence of electron-deficient
C¸C bonds in the CF3-substituted substrates (1b and 1l), which
may lead to favorable interactions with low-valent palladium
complexes through stronger back donation for 1a relative to 1j.
The role of Zn in these reactions is also worth discussing.
The addition of metallic Zn is supposed to reduce Pd(OAc)2 to
Pd(0) under potentially concomitant formation of Zn(OAc)2,
which may affect the course of the reaction by interacting with
the alkynoxy group. Therefore, we examined the effect of
Zn(OAc)2 on a reaction that used the preformed catalyst
Pd(PCy3)2 (Figure 5).40 In the absence of Zn(OAc)2, 6aa was
obtained in 6% yield after 10 min, while complete conversion
required more than 90 min. However, the addition of a catalytic
amount of Zn(OAc)2 accelerated the reaction, and 6aa was
obtained in 36% yield after 10 min, while complete conversion
was achieved within 60 min. This result suggested that the
in situ formation of the Pd(0) catalyst from Pd(OAc)2 and Zn
may be beneficial for this reaction.
D
TIPS
H/D
O
Pr
Pr
Pr
H
(5a, 1.5 equiv)
Pr
6ga(8-D)
O
Pd(PCy3)2 (5 mol%)
+
ð9Þ
H
TIPS
TIPS
C6D6, 90 °C, 6 h
D
O
H/D
1g-d1
Pr
Pr
6ga(2-α-D)
6ga(8-D) : 6ga(2-α-D) = 3.2 : 1
On the basis of these observations, it still remained unclear
if the cleaved hydrogen is transferred onto the product in a
unimolecular manner. In order to obtain an unambiguous
answer to this question, we examined a crossover experiment
between 1a and 1h-d5 and 5a. The reaction was catalyzed by
Pd(PCy3)2 and we found that part of the deuterium in 1h-d5 was
transferred onto 1a-derived product 6aa-d1 (48% D at the 2-
methylidene position; eq 10). This result indicated that this
C-H activation/transfer reaction does not proceed in a uni-
molecular fashion. It should be mentioned that D-H scrambling
at the C8-position was not observed, suggesting that the C-H
cleavage is irreversible. Indeed, when the competition reaction
between 1a and 1h-d5 was stopped after 30 min, 1a could be
recovered in 70% yield with hydrogen remaining at the ortho-
position.
Pr
Pr
(5a, 1.5 equiv)
Pd(PCy3)2 (5 mol%)
1a
0.5 equiv
1h
-d5
0.5 equiv
+
toluene, 90 °C, 17 h
48% D
TIPS
57% D
TIPS
O
O
H/D
H/D
ð10Þ
+
D4
MeO
Pr
Pr
Pr
Pr
6aa-d1, 94%
6ha-d5, 74%
Bull. Chem. Soc. Jpn. 2015, 88, 1388–1403 | doi:10.1246/bcsj.20150180
© 2015 The Chemical Society of Japan | 1397

O
H
3
4
R3
TIPS
R3 = 4-OMe (1a), 4-CF3 (1b)
3-OMe (1j), 3-CF3 (1l)
TIPS
H
O
Pd(PCy3)2 (5 mol%)
toluene, 90 °C
7
6
R3
+
Pr
Pr
Pr
Pr
5a (1.5 equiv)
R3 = 6-OMe (6aa), 6-CF3 (6ba)
7-OMe (6ja), 7-CF3 (6la)
time/min
time/min
Figure 3. Time-dependent conversion for the reaction between 1a (4-MeO), 1b (4-CF3), 1j (3-MeO), or 1l (3-CF3) and 5a.
a) : yield of 6aa (6-MeO, bold). : yield of 6ba (6-CF3, dashed). b) : yield of 6ja (7-MeO, bold). : yield of 6la (7-CF3,
dashed).
Based on our working hypothesis and the experimentally
obtained results, we would like to suggest a plausible catalytic
cycle for the reaction with alkynes employing the conditions
using Pd(OAc)2, PCy3, and Zn, which is illustrated in Figure 6.
Reduction of Pd(OAc)2 with Zn should provide a palladium(0)
complex and Zn(OAc)2. Initially, the C¸C bond in 1 should
coordinate to the palladium(0) center, thus generating π-
alkynoxy-coordinated complex v, which would be transformed
into zwitterionic complex vi coordinated to Zn(OAc)2. For this
C-H activation, two probable pathways are available.41-43 The
first comprises an electrophilic attack of Pd+ onto the ortho-aryl
carbon atom, resulting in the formation of palladacycle vii,
which should subsequently undergo a 1,2-hydrogen shift from
the ortho-carbon atom to the palladium center thus giving the
product of the oxidative addition (ix). The other possibility is an
intramolecular oxidative addition of the ortho-C-H bond onto
the cationic palladium center via an effective agostic interaction,
which would generate a hydridopalladium(IV) complex (viii),
which could release a vinylcarbon ligand to afford ix. These
two complexes vii and viii may be formed effectively by the
interaction with Zn(OAc)2. Thus, it is reasonable to assume that
Zn(OAc)2 acts as a simple Lewis acid that is coordinated by the
alkynoxy moiety to enhance the electrophilicity of the alkynoxy
moiety. This should strongly promote the formation of vi and
increase the high electron-deficiency of the palladium center,
effecting a facile C-H cleavage via the proposed pathways. The
deuterium-labelling experiments suggested that the hydrogen
migration step (vii or viii ¼ ix) is the rate-determining step.
The observed H-D scrambling indicated that the migration of
ortho-hydrogen may take place both intra- and intermolecularly,
until the oxidative addition is complete. Complex ix may
undergo two insertion pathways. Alkenyl palladium hydride
x may be initially generated via insertion of alkyne 5 into the
aryl-palladium bond of ix prior to the intramolecular carbo- or
hydropalladation of the C¸C bond to furnish alkenylpalladium-
hydride (xi) or palladacycle (xii) intermediates. Reductive
elimination of 6 from either xi or xii should regenerate the
palladium(0) complex and thus complete the catalytic cycle.
Alternatively, the intramolecular insertion of ix could result in
the formation of 5-membered palladacycle xiii, which should
undergo insertion of alkyne 5 to afford xii. A subsequent
reductive elimination should then provide 6.44 When alkyl/aryl
acetylenes are employed, plausible π-stacking interaction as in
e.g. xiv (Figure 7) should manifest between the aryl rings of
1 and 5 and thus favor the formation of 6 (R1 = Ar). Sterically
biased alkynes such as 5g could coordinate with arylpalladium
to form xv in such a direction that steric repulsion between
bulky R2 and the aryl group in ix is minimized.
1398 | Bull. Chem. Soc. Jpn. 2015, 88, 1388–1403 | doi:10.1246/bcsj.20150180
© 2015 The Chemical Society of Japan

5a (1.1 equiv)
Pd(dba)2 (5 mol%)
PCy3 (10 mol%)
O
O
+
TIPS
TIPS
toluene, 90 °C
MeO
H
F3C
H
1a (1 equiv)
1b (1 equiv)
TIPS
TIPS
O
O
H
H
+
Pr
Pr
MeO
F3C
Pr
Pr
6aa
6ba
time/h
5a (1.1 equiv)
Pd(PCy3)2 (5 mol%)
MeO
O
F3C
O
H
+
TIPS
TIPS
toluene, 90 °C
H
1j (1 equiv)
1l (1 equiv)
TIPS
H
TIPS
MeO
O
F3C
O
H
+
Pr
Pr
Pr
Pr
6ja
6la
time/h
Figure 4. Time-dependent conversion for the reaction between 1a (4-MeO) and 1b (4-CF3), as well as between 1j (3-MeO) and 1l
(3-CF3) and 5a. a) : yield of 6aa (6-MeO, bold). : yield of 6ba (6-CF3, dashed); catalyst: [Pd(dba)2]/PCy3. b) : yield of 6ja
(7-MeO, bold). : yield of 6la (7-CF3, dashed); catalyst: Pd(PCy3)2.
Further synthetic transformations of the obtained products
are outlined in Scheme 4. When using NiCl2(PCy3)2/PCy3
(Dankwardt conditions),45 the aryl-OMe bond in 6aa can be
cross-coupled with (p-tolyl)MgBr to provide 19 in 57% yield,
whereby the cyclic aryl-O bond remains intact. Given the
importance of benzo-1-pyrylium salts and 2,2-disubstituted 2H-
1-chromenes in the context of solar cell materials,46,47 we
examined the construction of such structures. Reaction of 6aa
with HBr in acetic acid furnished benzopyrylium bromide 20,
which was subsequently treated with n-BuMgBr¢LiBr in i-
Pr2O to form the corresponding 1,2-adduct, i.e. 2-butylated 2H-
1-chromene 21 as well as the 1,4-adduct 21¤ in 85% (72:28)
combined yield.
Conclusion
This study has demonstrated that the palladium(0)-catalyzed
double insertion/annulation of alkynyl aryl ethers with inter-
nal alkynes proceeds to give 2-methylidene-2H-chromenes via
activation of ortho-C-H bonds, and that this reaction mode
contrasts to that of terminal alkynes. The alkynoxy moiety plays
a key role as a directing group in this ortho-C-H activation/
annulation sequence. A broad variety of alkynyl aryl ethers and
Bull. Chem. Soc. Jpn. 2015, 88, 1388–1403 | doi:10.1246/bcsj.20150180
© 2015 The Chemical Society of Japan | 1399

O
H
TIPS
H
TIPS
Pd(PCy3)2 (5 mol%)
Zn(OAc)2 (0 or 5 mol%)
O
MeO
1a
toluene, 90 °C
+
MeO
Pr
Pr
Pr
Pr
6aa
5a (1.5 equiv)
time/min
Figure 5. Time-dependent conversion for the Pd(PCy3)2-catalyzed reaction of 1a with 5a in the presence (5 mol %, solid line) or
absence (dash line) of Zn(OAc)2.
Si
O
H
O
Si
PdLn
Zn(OAc)2
R2
6
R1
H
v
Si
O
O
H
Ph
Zn(OAc)2
1
Si
PdLn
vi
Si
Si
Si
H
O
O
PdLn
O
Zn(OAc)2
and/or
PdLn
R2
H
R2
PdLn
Si
R1
H
R1
xii
O
vii
5
Zn(OAc)2
xi
Pd
H
L
viii
Si
O
Zn(OAc)2
Pd
Ln
H
O
Si
L Pd H
O
xiii
Si
R2
Pd
H
R1
L
ix
x
R1
R2
L = PCy3
5
Figure 6. Proposed catalytic cycle for the Pd(0)-mediated alkynoxy-directed annulation of alkynyl aryl ethers with internal alkynes.
internal alkynes can be successfully converted by this annula-
tion. Moreover, it is possible to use 1,4-bisalkynoxyarene,
which is converted into condensed cyclic products. Norbornene
and norbornadiene can be used in this insertion/annulation
sequence, forming chromanes. Deuterium-labeling experiments
showed that the ortho-C-H bond is cleaved selectively by
palladium(0), and that this hydrogen atom is incorporated
at the 2-methylidene position of the products. The oxidative
addition of the C-H bond was identified as the rate-determining
step. Optimized reaction conditions comprise the ternary
1400 | Bull. Chem. Soc. Jpn. 2015, 88, 1388–1403 | doi:10.1246/bcsj.20150180
© 2015 The Chemical Society of Japan

TIPS
Pr
TIPS
Pr
(p-tolyl)MgBr
O
O
Ni cat.
a
MeO
6aa
Pr
Pr
19, 57%
HBr in AcOH
CH2Cl2, rt
b
Br
Pr
nBuLi
MgBr2
O
O
O
Bu
+
iPr2O, rt
MeO
Pr
MeO
Pr
MeO
c
Pr Bu
Pr
Pr
20, quantitative
21
21'
85% (72:28)
Scheme 4. Subsequent synthetic transformations of 6. Reagents and conditions: a) 6aa (1.0 equiv), (p-tolyl)MgBr (6.0 equiv),
i
NiCl2(PCy3)2 (5 mol %), PCy3 (10 mol %), Pr2O, 60 °C, 16 h; b) 6aa (1.0 equiv), HBr in AcOH (2 equiv, ca. 5.1 M), CH2Cl2
n
(1.0 M), rt, 2 h; c) BuLi (in hexane, 5 equiv with respect to 6aa), MgBr2 (5 equiv), iPr2O, rt, 23 h.
O
O
2002, 124, 13976. b) T. Xu, G. Dong, Angew. Chem., Int. Ed.
2012, 51, 7567.
L
L
Si
Si
5
Y. Kawasaki, Y. Ishikawa, K. Igawa, K. Tomooka, J. Am.
Chem. Soc. 2011, 133, 20712.
For recent reviews, see: a) F. Kakiuchi, T. Kochi, Synthesis
Pd
Pd
H
R2
H
6
2008, 3013. b) O. Daugulis, H.-Q. Do, D. Shabashov, Acc. Chem.
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Chiba, Chem. Lett. 2012, 41, 1554. n) G. Yan, X. Wu, M. Yang,
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xiv
xv
Figure 7. Proposed intermediates xiv and xv.
catalyst system Pd(OAc)2/PCy3/Zn, which most likely gener-
ates Zn(OAc)2 as a reaction rate-accelerating cocatalyst. The
obtained reaction products are furthermore susceptible to
additional synthetic modifications. Treatment of the annula-
tion products with hydrogen bromide furnished benzopyrylium
bromides, which can be converted into 2,2-dialkyl-2H-
chromenes and 4,4-dialkyl-4H-chromenes by the addition of
Grignard reagents. Currently, our research efforts focus on
extensions of the presented reaction system.
This work has been supported financially by a grant-in-aid
for scientific research (S) (No. 21225005 to T.H.) and a grant-
in-aid for young scientists (B) (No. 25870747 to Y.M.) from
the JSPS. Y.M. would also like to acknowledge the Asahi Glass
Foundation.
Supporting Information
Experimental procedures, characterization data, and copies
of 1H and 13C NMR spectra for all new compounds. This mate-
rial is available electronically on J-STAGE.
7
For a review, see: a) P. Gandeepan, C.-H. Cheng, Chem.®
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40 Additive of metallic Zn instead of Zn(OAc)2 did not affect
the reaction rate, suggesting that metallic Zn can only accelerate
the reaction with norbornene.
41 Our proposed mechanism is also consistent with
theoretical study reported by Meng and Wang; see: Q. Meng, F.
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42 For the oxidative addition of ortho-C-H bonds in anisole to
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43 The addition of the 2-C-H bond in indenes to alkynes,
catalyzed by the hydrido-bridged dinuclear palladium complex
[Pd2R2(¯-OH)(¯-dpfam)] [dpfam: N,N¤-bis[2-(diphenylphos-
phino)phenyl]formamidinate] was reported by Tsukada. This
reaction proceeds via an oxidative addition of C-H bonds to one
of the palladium centers; see: a) N. Tsukada, T. Mitsuboshi, H.
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a
47 For examples of a 1,2-addition between 1-benzopyrylium
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Bull. Chem. Soc. Jpn. 2015, 88, 1388–1403 | doi:10.1246/bcsj.20150180
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